Otitis media or middle ear infection is a common disease in childhood; in the United States, it is the most frequent reason for antibiotic use in children and pediatric office visits. Typically when children have otitis media it is usually acute. This means the duration of infection since the start of symptoms is under two weeks, and there is inflammation such as redness of the eardrum and pus in the middle ear, with or without the perforation of the eardrum (a hole in the eardrum).

In such cases, what causes the infection is usually a common bacterium such as Streptococcus pneumoniae (“strep”) or Haemophilus influenzae (including type B, or Hib). The infection can become chronic, so there is a persistent perforation that may not heal and a chronic or recurrent ear discharge.

Otitis media is typically treated with antibiotics and may require surgery. If left untreated, it can lead to complications, the most common of which is hearing loss. Today, there is a preventative vaccination available for bacteria (strep and some Hib) that cause acute otitis media.

Aside from young age, there are many risk factors that contribute to otitis media, such as lack of breastfeeding, allergies, upper respiratory infection, daycare attendance or overcrowding, exposure to tobacco smoke, low socioeconomic status, and family history. Over the past few years, the availability of new sequencing technologies has sped up the identification of novel genes associated with disease including infections and immune states.

Through funding from Hearing Health Foundation, our group studied an indigenous Filipino community that is relatively homogeneous, highly intermarried, and has about a 50 percent prevalence of otitis media. In this population quantitative age, sex, body mass index, breastfeeding, tobacco exposure or swimming in deep seawater were not associated with otitis media. All members of the indigenous community have poor access to health care and low socioeconomic status.

By using next-generation sequencing in two indigenous second cousins who have chronic otitis media, we identified a mutation in the A2ML1 gene that is shared by the two cousins. This gene encodes a protease inhibitor localized to the middle ear epithelium. (An inhibitor is a compound that traps protease—an enzyme that breaks up protein—and brings it to other cell structures for clearance.)

In this study, we reconstructed a large pedigree of 37 indigenous relatives with different forms of otitis media, and showed that each relative with the mutation has an 80 percent chance of having any form of otitis media. When the study was expanded to 85 community members, the A2ML1 mutation was the only significant predictor of otitis media within the community, and carriage of the mutation increases the risk of otitis media almost four-fold. Our study was published in American Academy of Otolaryngology–Head and Neck Surgery Foundation's journal on August 2, 2016.

Among A2ML1 mutation carriers, otitis media may be diagnosed within the first months of life, with chronic otitis media occurring in later childhood and persisting well into adulthood, suggesting that the mutation affects otitis media onset and recovery. Furthermore, mutation carriers with chronic otitis media have higher relative abundance of the bacteria Fusobacterium and Porphyromonas, which are relatively uncommon for the disease.

Taken together, these findings are consistent with the role of A2ML1 protein as a protective factor in the middle ear; defective A2ML1 protein makes the middle ear mucosa susceptible to damage from proteases produced by both bacteria and inflammatory cells. The mutation of the gene means its protease inhibitor action fails to trap and clear damaging enzymes.

Remarkably the same A2ML1 mutation that was found in the indigenous Filipinos was also identified in three European and Hispanic-American children, indicating that this mutation is not limited to the Filipinos. (It’s possible the same ancestor from Spain, estimated to be 1,800 years ago, introduced the variation to these populations.) The three U.S. children who carried the mutation also had early-onset otitis media that required surgery by six months. Additionally we also identified rare A2ML1 mutations in six other otitis-prone children in the U.S.

We have established A2ML1’s involvement in otitis media susceptibility and can use this knowledge to predict otitis media occurrence in mutation carriers. Now we are expanding our research by studying DNA and/or microbial samples from additional U.S. and Filipino families, and RNA and additional microbial samples from the indigenous Filipino population. Our goal is to identify additional genes and pathways that play a role in otitis media susceptibility and that may be targeted to develop novel treatments of chronic otitis media.

Regie Lyn P. Santos-Cortez, M.D., Ph.D., is an associate professor in the Department of Otolaryngology, University of Colorado Denver, Anschutz Medical Campus. A 2011 and 2012 Emerging Research Grants scientist, she also received the 2012 Collette Ramsey Baker Research Award (in memory of Collette Ramsey Baker, HHF’s founder).